Liver cancer is the second leading cause of death related to cancer worldwide, and hepatocellular carcinoma (HCC) accounts for between 85% and 90% of liver cancer. Almost 70% to 80% of hepatocellular carcinoma is discovered only after it is progressed into an advanced stage. At present, there is only Sorafenib as a medicine which is approved as a therapeutic agent specific to advanced hepatocellular carcinoma.
Major cause of HCC is liver cirrhosis. Since there are many causes of having liver cirrhosis such as hepatitis caused by hepatitis viruses (i.e., HBV or HCV), alcohol consumption, or non-alcoholic fatty liver, it is difficult to lay out a strategic plan for treating a patient with HCC based on personal history of liver cirrhosis alone.
It has been known that various pathways including Wnt-β-catenin pathway, p53-Rb pathway, chromatin remodeling and phosphatidylinositol 3-kinase (PI3K)-AKT are related with an onset of HCC (El-Serag H B, Rudolph K L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007; 132: 2557-76; Schulze K, Imbeaud S, Letouze E, Alexandrov L B, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015; 47: 505-11). However, in spite of the results of those studies, the major determinant of the advance from early HCC to advanced HCC (i.e., GII HCC and GIII HCC) is yet to be identified.
Idelalisib is a PI3K inhibitor and a medicine approved by US FDA and European Medicines Agency as a therapeutic agent for late relapsed Non-Hodgkin's B-cell lymphoma. Upon binding to the ATP-binding site of p110δ, this inhibitor inactivates the PI3K-AKT signal transduction pathway. Activation of the PI3K pathway is mediated by class I PI3K catalytic isotypes p110α, p110β, p110δ, and p110γ. p110δ is predominantly expressed in hematopoietic stem cells, and the PI3K-AKT signal transduction basically contributes to immune cell proliferation and stimulation of related cytokines and chemokines. Accordingly, with regard to idelalisib, until now the focus is on cell survival, in particular, death of immune cells.
Korean Patent Application Publication No. 10-2014-0022836 is related to combination therapies for hematologic malignancies, and it discloses a use of idelalisib for treating lymphoblastic leukemia. However, nothing is known about the role played by idelalisib in liver cancer, in particular, advanced hepatocellular carcinoma, and development of a therapeutic agent for advanced hepatocellular carcinoma is in need.